Efficacy and safety of long-term maraviroc use in a heterogeneous group of HIV-infected patients: A retrospective cohort study.

Since the registration of maraviroc (MVC) as an antiretroviral agent in 2008, only studies with a follow-up time of <5 years have been published. Therefore, little is known about its long-term safety and efficacy in clinical practice. In this cohort study, data on long-term follow-up of MVC treatment in routine practice were analysed. A retrospective cohort study was conducted at University Medical Centre Utrecht with a follow-up period up to almost 10 years. The efficacy and tolerability of MVC-containing antiretroviral therapy (ART) was analysed in human immunodeficiency virus type 1 (HIV-1)-infected patients. The cohort consisted of 111 HIV patients who were treated for a median of 11.0 years (IQR 4.0-15.0 years) and with a median of 4 (IQR 2-6) previous ART regimens. The median time of MVC use was 49 months (IQR 21-82 months). Mean CD4+ T-cell counts continued to increase up to 9 years following initiation of MVC. Patients with a detectable viral load (≥50 copies/mL HIV-RNA) at the start of MVC-containing ART reached high proportions of viral suppression. Only three patients (2.7%) experienced treatment failure despite optimal therapy. Nine patients (8.1%) discontinued MVC owing to intolerance of their ART regimen. Severe laboratory abnormalities were deemed to be unrelated to MVC use. During the 487 person-years of follow-up, 18 patients (16.2%) died. MVC use in this heavily pre-treated cohort was generally well tolerated during long-term follow-up. Furthermore, use of MVC resulted in a good immunological and virological response in clinical practice.

Factors associated with time to achieve an undetectable HIV RNA viral load after start of antiretroviral treatment in HIV-1-infected pregnant women.

OBJECTIVE: To identify factors associated with the time to viral suppression in women starting antiretroviral treatment (ART) during pregnancy. Knowledge on duration of viral load (VL) decline could help deciding the timing of treatment initiation. METHODS: Highly active antiretroviral treatment (HAART)-naive pregnant women over 18 years of age who started treatment during pregnancy were included. The time to viral suppression was calculated and compared between subgroups. RESULTS: A total of 227 pregnancies matched our inclusion criteria. In 84.6% of these an undetectable VL was reached at the time of delivery. The median time to undetectable VL after initiation of treatment was 60 days (12-168 days). Only baseline VL <10,000 copies/mL showed an independent association with time to viral suppression in multivariate Cox regression analysis, with a mean time to reach a VL <50 HIV-1 copies/mL of 49 days (95% CI 44-53). No difference in time to undetectable VL was found between protease inhibitor and non-nucleoside reverse transcriptase inhibitor-based regimens. Integrase inhibitors were not part of any treatment regimen. CONCLUSION: Our results suggest that in patients with baseline HIV RNA <10,000 copies/mL ART initiation might be postponed up to the twentieth week of pregnancy, thus minimising the risk of possible drug-related teratogenicity and toxicity.

Efficacy of tenofovir and efavirenz in combination with lamivudine or emtricitabine in antiretroviral-naive patients in Europe.

BACKGROUND: The combination of tenofovir and efavirenz with either lamivudine or emtricitabine (TELE) has proved to be highly effective in clinical trials for first-line treatment of HIV-1 infection. However, limited data are available on its efficacy in routine clinical practice. METHODS: A multicentre cohort study was performed in therapy-naive patients initiating ART with TELE before July 2009. Efficacy was studied using ITT (missing or switch = failure) and on-treatment (OT) analyses. Genotypic susceptibility scores (GSSs) were determined using the Stanford HIVdb algorithm. RESULTS: Efficacy analysis of 1608 patients showed virological suppression to <50 copies/mL at 48 weeks in 91.5% (OT) and 70.6% (ITT). Almost a quarter of all patients (22.9%) had discontinued TELE at week 48, mainly due to CNS toxicity. Virological failure within 48 weeks was rarely observed (3.3%, n = 53). In multilevel, multivariate analysis, infection with subtype B (P = 0.011), baseline CD4 count <200 cells/mm³ (P < 0.001), GSS <3 (P = 0.002) and use of lamivudine (P < 0.001) were associated with a higher risk of virological failure. After exclusion of patients using co-formulated compounds, virological failure was still more often observed with lamivudine. Following virological failure, three-quarters of patients switched to a PI-based regimen with GSS <3. After 1 year of second-line therapy, viral load was suppressed to <50 copies/mL in 73.5% (OT). CONCLUSIONS: In clinical practice, treatment failure on TELE regimens is relatively frequent due to toxicity. Virological failure is rare and more often observed with lamivudine than with emtricitabine. Following virological failure on TELE, PI-based second-line therapy was often successful despite GSS <3.

Delayed HIV testing in internal medicine clinics - a missed opportunity.

As HIV infection may be non-symptomatic for many years, many HIV-infected individuals are not aware of their infection. At a certain point in time non-specific symptoms may occur for which patients are likely be referred to internal medicine outpatient clinics. In the absence of systematic screening for HIV and in particular in patients who do not have classical risk factors for HIV, the diagnosis of HIV infection may easily be overlooked. In this manuscript it is illustrated that this diagnostic and therapeutic delay can lead to increased morbidity and mortality. Moreover, undiagnosed individuals are on average more likely to transmit HIV than diagnosed individuals. It is important for public health to identify people harbouring HIV infection, as this is expected to reduce the number of new infections. HIV infection should be considered a possible cause of unexplained symptoms in an early stage of the diagnostic process, in particular in patients with symptoms such as unexplained fever, lymphadenopathy or weight loss or in the presence of conditions suggestive of possible immune deficiency, regardless of the absence of risk factors.

No increased risk of hepatotoxicity in long-term use of nonnucleoside reverse transcriptase inhibitors in HIV-infected patients.

OBJECTIVE: The aim of this study was to assess the incidence of hepatotoxicity in patients who had used nonnucleoside reverse transcriptase inhibitors (NNRTIs) for at least 3 years. METHODS: The study group consisted of HIV-infected patients under follow-up at our clinic, who had continuously used an NNRTI-containing regimen (efavirenz or nevirapine) for at least 3 years. Patients who had used protease inhibitors (PIs) for the same time span constituted a control group. Hepatotoxicity was graded according to the modified AIDS Clinical Trial Group grading system, using alanine aminotransferase (ALT) as a marker. RESULTS: One hundred and twenty-two patients on an NNRTI regimen and 54 PI-using patients were included in the analysis. The mean follow-up time was nearly 6 years. Eighteen NNRTI-using patients (14.8%) developed a clinically relevant (≥ grade II) event of hepatotoxicity during treatment; five of them (4.1%) developed severe hepatotoxicity (≥ grade III). No significant difference in the hepatotoxicity rate was seen between NNRTI- and PI-using patients (14.8 vs. 18.5%, respectively; P = 0.52) or between patients using efavirenz and nevirapine (13.8% vs. 16.7%, respectively; P = 0.51). A hepatitis C virus (HCV) coinfection was associated with an increased risk of the development of hepatotoxicity during NNRTI therapy [odds ratio (OR) 1.83; 95% confidence interval (CI) 1.33-4.24; P < 0.01]. Finally, we observed that more hepatotoxic events occurred during the first year of NNRTI therapy compared with the entire period after 1 year (6.6 vs. 2.8 events, respectively, per 100 person-years of treatment; P = 0.04). CONCLUSIONS: Long-term NNRTI use was not associated with a higher risk of clinically significant liver toxicity in patients who had been treated with NNRTI for at least 3 years.

Short- and long-term outcome of HIV-infected patients admitted to the intensive care unit.

The purpose of this investigation was to analyse the impact of the availability of highly active antiretroviral therapy (HAART) on the long-term outcome of human immunodeficiency virus (HIV)-infected patients admitted to the intensive care unit (ICU). A retrospective cohort study of HIV-infected patients admitted to the ICU was undertaken. Outcomes in the pre-HAART era (1990-June 1996), early- (July 1996-2002), and recent-HAART (2003-2008) periods and total HAART era (July 1996-2008) were analysed and compared with those reported of the general population. A total of 127 ICU admissions were included. The 1-year mortality decreased from 71% in the pre-HAART era to 50% in the recent-HAART period (p = 0.06). The 5-year mortality decreased from 87% in the pre-HAART era to 59% in the early-HAART period (p = 0.005). Independent predictors of 1-year mortality in the HAART era were age (odds ratio [OR] = 1.16 [95% confidence interval [CI] = 1.06-1.27]), APACHE II score > 20 (6.04 [1.25-29.22]) and mechanical ventilation (40.01 [3.01-532.65]). The 5-year survival after hospitalisation was 80% and in the range of the reported survival of non-HIV-infected patients (83.7%). Predictors of 1-year mortality for HIV patients admitted to the ICU in the HAART era were all non-HIV-related. Short- and long-term outcome has improved since the introduction of HAART and is comparable to the outcome data in non-HIV-infected ICU patients.

[Osteonecrosis as late complication in HIV-infected patients]. / Osteonecrose als late complicatie bij hiv-geïnfecteerde patiënten.

Osteonecrosis of the femoral head was diagnosed in a 22-year-old woman and a 46-year-old man, both with HIV infection . Both had groin pain and impaired mobility. Conservative treatment did not relieve the pain. Both patients underwent a surgical procedure, i.e. core decompression and total hip replacement. In HIV-infected patients, osteonecrosis, i.e. avascular necrosis is an increasingly common problem in view of current longer life expectancy. The incidence of osteonecrosis is higher in HIV-infected patients than in the general population. Osteonecrosis should be included in differential diagnosis of groin or hip pain in HIV-positive patients. This may enable more rapid diagnosis and reduce the need for surgery.

HPV-related anogenital disease and HIV infection: not always 'ordinary' condylomata acuminata.

Human papillomavirus (HPV) is responsible for various diseases in the anogenital region which range from benign condylomata acuminata to anal carcinoma. Buschke-Loewenstein tumour is a clinically 'intermediate' condition which is histologically benign but due to extensive destruction of the local tissues can show malignant behaviour. Its early recognition as a different clinical entity to 'ordinary' condylomata acuminata is important for its adequate management. Immunocompromised persons, such as those with HIV infection, have a higher incidence of HPV-related anogenital disease. Different aspects of the HPV-related anogenital disease in HIV-positive individuals are discussed.

[Antibiotic prophylaxis not indicated in dental procedures in patients with a joint prosthesis]. / Antibioticaprofylaxe niet geïndiceerd bij tandheelkundige ingrepen bij patiënten met een gewrichtsprothese.

Antibiotic prophylaxis is suggested for high-risk patients undergoing dental procedures to prevent haematogenous infection of the artificial joint. However, randomised placebo-controlled trials are lacking. Case reports are difficult to interpret, because bacteraemias are very common after chewing and tooth brushing anyway. Widespread use of antibiotics has serious downsides. Therefore, more convincing data are needed to support the use of antibiotic prophylaxis for high-risk patients.

Carotid intima-media thickness in type 2 diabetes is more strongly related to serum apoprotein A-I in females.

BACKGROUND: Dyslipidemia in type 2 diabetes has been shown to be related to the incidence of macrovascular events. Increased carotid intima-media thickness is considered to be a marker of macrovascular disease. MAIN PURPOSE: To investigate a possible relationship between lipoprotein levels and carotid intima-media thickness as a marker of early atherosclerosis in patients with type 2 diabetes. METHODS: Seventy-one consecutively selected eligible patients (31 males, 40 females) with type 2 diabetes were studied. Common carotid intima-media thickness was measured bilaterally by high-resolution ultrasound and the mean value from both sides was used for further analysis. Fasting blood samples were taken from each individual and their serum was analyzed for lipoprotein levels. RESULTS: In the entire group of patients, intima-media thickness was inversely related to apoprotein A-I (r = -0.33, p = 0.008) and HDL cholesterol (r = -0.23, p = 0.059) in univariate correlation analysis, and a positive correlation between intima-media thickness and apoprotein B/apoprotein A-I ratio was found (r = 0.33, p = 0.007). When genders were analyzed separately, intima-media thickness was significantly correlated with apoprotein A-I and apoprotein B/apoprotein A-I ratio in females, while no significant correlation of any lipid variable with intima-media thickness was observed in males. In multiple linear regression analysis, age (p = 0.005), male gender (p = 0.002) and apoprotein A-I (p = 0.035) were the only risk factors in the entire group of diabetic patients, which significantly predicted carotid intima-media thickness in models adjusted for demographic and other known risk factors. As was the case in the univariate analysis, no risk factor significantly predicted carotid intima-media thickness in males while age, apoprotein A-I and B significantly predicted intima-media thickness in females. CONCLUSIONS: In the present study, low serum apoprotein A-I, a major protein component of HDL, was found to be related to increased carotid intima-media thickness. This relationship was stronger in females than in males, which suggests possible gender differences in the relationship between apoprotein A-1 and early atherosclerotic lesions in subjects with type 2 diabetes mellitus.

[Effect of bisoprolol on heart rate variability in patients with hyperthyroidism]. / Vplyv bisoprololu na variabilitu srdcovej cinnosti u chorých s hypertyreózou.

OBJECTIVE: The objective of the submitted work was to assess by the method of spectral analysis of the heart rate how the use of bisoprolol will affect the autonomous modulation of the heart rate in hyperthyroid patients and what are the time relations of this effect. MATERIAL AND METHODS: In the investigation 10 female patients with thyreotoxicosis caused by Graves-Basedow's disease were included. Their average age was 38 years and along with a thyrostatic drug bisoprolol was administered. Spectral analysis of the heart rate was made before the onset of treatment, after a week and after six weeks with the patients in an upright and recumbent position. The activity of the sympathicus was evaluated from the ratio of low and high frequencies. RESULTS: Already during the first week a significant decline of the heart rate was observed. During the first week of treatment a decline of the activity of the sympathicus in a recumbent position occurred associated with milder palpitations or their complete disappearance. The decline in an upright position occurred after the first week of treatment. From the trend of other parameters of cardiac variability, the differences of some reached statistical significance, it may be concluded that the activity of the parasympathicus, formerly inhibited, was restored. CONCLUSION: Based on the results it may be stated that bisoprolol is a suitable supplementary drug in the early treatment of thyrotoxicosis because by reducing the hyperadrenergic state it improves the quality of life of these patients.

Carotid intima-media thickness in relation to macrovascular disease in patients with type 2 diabetes mellitus.

BACKGROUND: Increased carotid intima-media thickness is regarded as a marker of atherosclerosis. Type 2 diabetes mellitus is associated with a high prevalence of macrovascular disease. MAIN PURPOSE: The present study aimed to examine the relationship between carotid intima-media thickness and the presence of macrovascular disease in patients with type 2 diabetes. METHODS: 71 patients with type 2 diabetes mellitus were studied. The distal common carotid artery and carotid bifurcation intima-media thickness were measured bilaterally with high-resolution ultrasonography. The relationship between the presence of coronary artery disease, cerebrovascular disease and peripheral arterial disease and carotid intima-media thickness was evaluated. RESULTS: Patients with coronary artery disease had significantly (p = 0.048) increased intima-media thickness of the distal common carotid artery. This difference ceased to be significant after adjustment for cardiovascular risk factors. Patients with peripheral arterial disease had a significantly higher bifurcation (p < 0.0001), distal common carotid (p = 0.03) and mean intima-media thickness (p = 0.0008) than did those without peripheral arterial disease. This difference remained significant even after adjustment for other cardiovascular risk factors. In the multiple linear regression analysis, the presence of peripheral arterial disease, age and male gender significantly predicted bifurcation intima-media thickness, while age and the presence of peripheral arterial disease significantly predicted mean intima-medial thickness. CONCLUSIONS: In the present study, the increased carotid intima-media thickness in patients with type 2 diabetes mellitus was related to the presence of peripheral arterial disease. This finding probably reflects morphologic and hemodynamic similarities between the two vascular beds and indicates that increased carotid intima-media thickness in patients with type 2 diabetes may be a marker of atherosclerosis in different locations.

Cardiovascular risk factors as predictors of mortality in type II diabetic patients.

BACKGROUND: Mortality among diabetic patients is high and attempts have been made to find clinical markers which would help to identify patients at risk. MAIN PURPOSE: The purpose of this study was to assess whether cardiovascular risk factors like previous myocardial infarction, left ventricular dysfunction, hypertension, renal insufficiency, and 24-hour mean or minimum heart rate, significantly contribute to the mortality in this group of patients. METHODS: 45 male patients with type II diabetes mellitus were studied by ambulatory electrocardiography to obtain the information about the 24-hour mean and minimum heart rates; records from baseline hospitalization were reviewed for clinical variables. After 55 months mortality data were retrieved. Cox's proportional hazards regression model was used to study the effect of clinical variables on mortality in multivariate analysis. RESULTS: All-cause mortality was 38%. The groups of survivors and nonsurvivors differed significantly in terms of age, the presence of left ventricular dysfunction and renal insufficiency. No significant difference in 24-hour mean or minimum heart rate was registered. In the Cox's model, the presence of left ventricular dysfunction, renal insufficiency and age significantly and independently predicted mortality. CONCLUSION: The present study, showed that left ventricular dysfunction and renal insufficiency were related to the all-cause mortality of type II diabetic patients independently of age, after 55 months of follow-up. Prognostic significance of 24-hour mean or minimum heart rate has not been proven.

[Infections of the diabetic foot--etiopathogenesis and possible preventive strategies]. / Infekcie diabetickej nohy--etiopatogenéza a mozné preventívne stratégie.

The St. Vincent declaration defined the aim to achieve within the next five years a 50% reduction of the number of amputations on account of diabetic gangrene. This can be achieved by systematic application of preventive and therapeutic provisions in practice. The authors mention the most important pathogenetic factors leading to the development of lesions of the lower extremities in diabetics as well as the most frequent microorganisms participating in their infection. They remind also of the most important preventive measures to be taken by patients and physicians.

[Infection of the diabetic foot--appropriate antibiotics and therapeutic strategies]. / Infekcie diabetickej nohy--vhodné antibiotiká a liecebná stratégia.

The authors give a review of the appropriate antibiotics used in the treatment of diabetic foot infection as well as the therapeutic strategies with regard for the severity of the infection and the expected pathogen. They also analyze some specific problems of antibiotic treatment in this group of patients.

[Noninvasive electrocardiographic monitoring and ventricular arrhythmias in patients after myocardial infarct]. / Neinvazívne elektrokardiografické sledovania a komorové arytmie u chorých po infarkte myokardu.

It is generally accepted that ventricular arrhythmias represent a predictor of prognosis after myocardial infarction, and that their impact on the increase of risk is especially unfavourable when associated with myocardial ischaemia or reduced left ventricular function. The aim of the study was to assess the significance and contribution of noninvasive ECG methods in detection of risk due to sudden cardiac death in Q postmyocardial infarction patients. Two-hundred and seventy patients were examined by exercise testing which in 5.2% of cases revealed couplet ventricular extrasystoles and 0.8% yielded non-sustained ventricular tachycardia. 24-hour-Holter ECG recording was performed in 168 patients (19.0% of couplet ventricular extrasystoles, 9.0% of non-sustained and 0.6% of sustained ventricular tachycardia respectively), and 300 patients were examined by late ventricular potentials analysis with a result of 25% positive cases. During 3 years of follow-up, 20 out of 300 patients (6.7%) died suddenly; in this group late ventricular potentials occurred significantly more frequently than in survivors. Exercise testing plays a major role in the detection of myocardial ischaemia, while Holter recording and signal averaging for detection of late ventricular potentials are important in noninvasive diagnosis of ventricular arrhythmias. Their combination with other ECG techniques (heart rate variability, QT dispersion) and determination of global function of the left ventricle may help to identify the group of patients in whom subsequent electrophysiological study is indicated in order to determine the optimal therapy for mortality reduction after myocardial infarction. (Fig. 5, Tab. 3, Ref. 20.)

[Changes in lipoprotein metabolism in patients with diabetes mellitus and the effect on lipid profile in diabetics]. / Niektoré zmeny metabolizmu lipoproteínov u chorých s diabetes mellitus a ich vplyv na lipidový profil diabetikov.

Diabetic patients have a 2 to 4 times higher risk of development of atherosclerosis than non-diabetic subjects. One of the risk factors of atherosclerosis is an impaired lipid and lipoprotein metabolism which is influenced by the type of diabetes, the degree of its metabolic compensation, character of treatment and other concurrently present metabolic abnormalities. In metabolically balanced type 1 diabetes the levels of commonly assessed lipoproteins do not differ from those in non-diabetic subjects, the HDL-cholesterol level can be even higher. The lipid profile of type 2 diabetics is not very homogeneous, however, usually elevated levels of VLDL-triglycerides and of apoprotein B and a reduced HDL-cholesterol level are found. At present there are no unequivocal views on the role of the lipoprotein (a) ratio in the increased risk of atherosclerosis in diabetics as investigations devoted to the lipoprotein (a) level and its relation to macrovascular complications in diabetes did not give unequivocal results. The scope of dyslipidemia in diabetics with nephropathy is in addition to the effect of the basic disease influenced also by the extent of renal damage. The lipid disorder, on the other hand, leads to deterioration of albuminuria and progression of the renal disease.

[Factors affecting serum lipid levels in patients with type 2 diabetes mellitus]. / Faktory ovplyvnujúce sérové koncentrácie lipidov u chorých s diabetes mellitus 2. typu.

Serum lipid concentrations were assessed in 147 type 2 diabetics. The patients were divided into different sub-groups in order to follow up different factors which could have an impact on serum lipids. The mean total cholesterol concentrations were significantly higher in diabetic women as compared with men. The authors did not reveal significant differences in lipid concentrations between obese and non-obese diabetics. Hypertensive diabetics had higher mean total cholesterol levels and LDL-cholesterol levels, as compared with diabetic patients without hypertension. Patients using oral antidiabetics had significantly higher mean triglyceride levels and lower HDL-cholesterol levels, as compared with insulin-treated diabetics. In a multiple stepwise regression analysis correlated triglycerides with three independent variables: total cholesterol, diastolic blood pressure and inversely with HDL-cholesterol. On the other hand, total cholesterol correlated significantly with triglycerides, HDL-cholesterol and proteinuria/day. To sum up, it may be stated, that the results of the present investigation are consistent with Reaven's concept of the syndrome X, however the cholesterol concentration is affected also by the proteinuria.